Landau-Kleffner syndrome: genes and variants

Genes linked to Landau-Kleffner syndrome

• GRIN2A: Glutamate receptor ionotropic, NMDA 2A

  It helps determine the kinetics and signaling properties of NMDA receptors, particularly in cortical circuits involved in language and epilepsy. Pathogenic variants cause a spectrum of developmental epileptic encephalopathies and epilepsy-aphasia disorders.

  85 disease-causing and 638 uncertain variants in GRIN2A are linked to Landau-Kleffner syndrome.

Weakly linked (only a few uncertain records): GRIN2B.

Where Landau-Kleffner syndrome variants cluster

• GRIN2A Extracellular (positions 647–814): 30 of 85 disease-causing changes, 3.1× more than its size predicts.
• GRIN2A Transmembrane (positions 626–646): 6 of 85 disease-causing changes, 4.9× more than its size predicts.
• GRIN2A Transmembrane (positions 815–835): 6 of 85 disease-causing changes, 4.9× more than its size predicts.
• GRIN2A Pore-forming (positions 599–620): 5 of 85 disease-causing changes, 3.9× more than its size predicts.

Known disease-causing variants in Landau-Kleffner syndrome

Showing 60 of 85.

Uncertain variants in Landau-Kleffner syndrome that look disease-causing

Which prediction tools work for Landau-Kleffner syndrome

How often each tool ranks a disease-causing variant above a harmless one (AUROC × 100).

• EVE: 98 out of 100
• AlphaMissense: 95 out of 100
• PolyPhen-2: 88 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• SIFT: 86 out of 100
• MetaLR: 85 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• CADD: 84 out of 100
• REVEL: 83 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• MutPred2: 82 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• phyloP: 70 out of 100
• CATVariant: 66 out of 100 (learned from overlapping clinical labels, so this is optimistic)

Diseases related to Landau-Kleffner syndrome

• Alzheimer disease, also linked to GRIN2A
• Epilepsy, also linked to GRIN2A
• Self-limited epilepsy with centrotemporal spikes, also linked to GRIN2A
• Schizophrenia, also linked to GRIN2A
• Dementia, also linked to GRIN2A
• Parkinson disease, also linked to GRIN2A
• GRIN2A-related complex neurodevelopmental disorder, also linked to GRIN2A

Frequently asked questions

Which genes are linked to Landau-Kleffner syndrome?

In CATVariant, Landau-Kleffner syndrome is linked to 1 analyzed protein: GRIN2A (Glutamate receptor ionotropic, NMDA 2A).

How many genetic variants are linked to Landau-Kleffner syndrome?

897 variants: 85 are classified as disease-causing (pathogenic or likely pathogenic) in ClinVar and 639 are of uncertain significance or have conflicting reports.

Which uncertain variants in Landau-Kleffner syndrome look disease-causing?

7 uncertain variants reach the likely-pathogenic range of the ACMG/AMP points scale on computable evidence, for example GRIN2A A818T, GRIN2A A638V, GRIN2A A716D, GRIN2A A647G and GRIN2A G532E. These are leads for expert review, not diagnoses.

Which variant effect predictor works best for Landau-Kleffner syndrome?

Among tools not trained on clinical labels, EVE separates this disease's known disease-causing variants from harmless ones best (AUROC 0.98, based on 59 disease-causing and 12 harmless variants).

About this data

Variant–disease links come from ClinVar, Open Targets and UniProt, pooled from the latest public CATVariant analysis of each human protein. Evidence scores use the ACMG/AMP Bayesian points scale with computable criteria only (position among known disease variants, rarity in gnomAD, calibrated predictors, deep mutational scanning); there is no family or patient data, so they prioritise variants for expert review and never classify them.

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